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Imaging Cellular Networks and Protein-Protein Interactions In Vivo
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Snehal Naik, Britney L. Moss, David Piwnica-Worms, Andrea Pichler-Wallace
Other transcriptional read-out strategies exist that offer variations on the system described above that may be better suited to the properties of the proteins of interest. The split-ubiquitin system enables signal amplification from a transcription factor-mediated reporter readout (11,12). In one application, the interaction of two membrane proteins forces reconstitution of two halves of ubiquitin, leading to a cleavage event mediated by ubiquitin-specific proteases that release an artificial transcription factor to activate an imageable reporter gene. In the cytokine-receptor-based interaction trap method, a signaling-deficient receptor provides a scaffold for recruitment of interacting fusion proteins that phosphorylate endogenous signal transducers and activators of transcription-3 (STAT3). Activated STAT complexes then drive a nuclear reporter (13). This system permits detection of both modification-independent and phosphorylation-dependent interactions in intact mammalian cells, but the transcriptional readout again limits kinetic analysis. As mentioned above for conventional two-hybrid systems, the indirect readout of the reporter limits kinetic analysis, and the released transcription factor must translocate to the nucleus.
Targeting SOX2 in anticancer therapy
Published in Expert Opinion on Therapeutic Targets, 2018
Laura Hüser, Daniel Novak, Viktor Umansky, Peter Altevogt, Jochen Utikal
A study on lung and esophageal squamous cell carcinoma used an interesting technique to target SOX2. The authors established a zinc finger-based artificial transcription factor, which allowed them to selectively suppress SOX2 in cancer cells while the viability of normal human cells was not influenced. Hence, the authors suggested using this artificial transcription factor for anticancer targeted therapy in lung and esophageal squamous cell carcinoma [76]. The same technique was also shown in breast cancer to target SOX2. The use of zinc finger-based artificial transcription factor targeting SOX2 results in decreased cancer cell proliferation and colony formation in vitro and inhibited breast cancer cell growth in vivo. The authors suggested using this technique in cancer therapy to obtain a long lasting downregulation of oncogenic transcription factors [77].
Peptides, proteins and nanotechnology: a promising synergy for breast cancer targeting and treatment
Published in Expert Opinion on Drug Delivery, 2020
Anabel Sorolla, Maria Alba Sorolla, Edina Wang, Valentín Ceña
NPs represent an excellent strategy to protect therapeutic peptides from degradation, to preserve their native structure and to conduct their action to the site of interest [99,100]. Therapeutic peptides able to control gene expression by blocking the action of transcription factors are not exempted from the need of nanotechnology for preserving peptide integrity and facilitate the reach of the nuclear target. These peptides, also known as interference peptides (iPeps), are shorter or same-size versions of a transcription factor encompassing a few mutations that makes them inert but able to sequester their binding partners with high affinity which leads to the shutdown of the transcriptional program [100] (Figure 2). In our laboratory, we have designed iPeps against transcription factors responsible for tumor development, stemness and drug resistance in BC, e.g. EN1 [20] and MYC [11]. With the aim to deliver EN1-iPeps in the cell nucleus, we have made us of polymeric NPs made of poly(glycidyl) methacrylate (PGMA) [7,10] and the linkage of the EN1-iPeps to the CPP SV40 [20,97]. Later, RGD sequences were added to the EN1-iPeps to enhance tumor selectivity of docetaxel PGMA NPs and reduced tumor growth while not eliciting systemic toxicity in mice [7]. This clearly shows the utility of NPs to deliver interference peptides against specific oncogenic transcription factors in vivo. Other authors have reported proof-of-concept studies where they show the benefit of nanomaterials to encapsulate artificial transcription factors to modify gene expression. For example, Patel et al developed NanoScript, an artificial transcription factor made of DNA binding and activation domains, cell penetrating peptides assembled on gold NPs. Such platform increased the expression of a reporter plasmid by 15-fold [101]. Also, Liu et al engineered supramolecular NP made of polyamidoamine functionalized with the CPP TAT [102], PEG and RGD peptides and encapsulating the transcription factor GAL4‐VP16 together with a luciferase reporter plasmid. Such NP demonstrated successful induction of luciferase upon internalization in HeLa cells [103].